CLINICAL PHARMACY IN PULMONOLOGY
Clinical Pharmacy in pulmonology. Symptoms and syndromes of major respiratory diseases. Clinical pharmacology of drugs used to treat obstructive lung diseases
ASTHMA
Asthma is an airway disorder characterized by bronchoconstriction, inflammation, and hyperreactivity to various stimuli. Resultant symptoms include dyspnea, wheezing, chest tightness, cough, and sputum production. Wheezing is a highpitched, whistling sound caused by turbulent airflow through an obstructed airway. Thus, any condition that produces significant airway occlusion can cause wheezing. However, a chronic cough may be the only symptom for some people.
Symptoms vary in incidence and severity from occasional episodes of mild respiratory distress, with normal functioning between “attacks,” to persistent, daily, or continual respiratory distress if not adequately controlled. Inflammation and damaged airway mucosa are chronically present, even when clients appear symptom free.
Acute symptoms of asthma may be precipitated by numerous stimuli, and hyperreactivity to such stimuli may initiate both inflammation and bronchoconstriction. Viral infections of the respiratory tract are often the causative agents, especially in infants and young children whose airways are small and easily obstructed. Asthma symptoms may persist for days or weeks after the viral infection resolves. In about 25% of patients with asthma, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate an attack. Some patients are allergic to sulfites and may experience life-threatening asthma attacks if they ingest foods processed with these preservatives (eg, beer, wine, dried fruit). The Food and Drug Administration (FDA) has banned the use of sulfites on foods meant to be served raw, such as open salad bars. Patients with severe asthma should be cautioned against ingesting food and drug products containing sulfites or metabisulfites. Gastroesophageal reflux disease (GERD), a common disorder characterized by heartburn and esophagitis, is also associated with asthma. Asthma that worsens at night may be associated with nighttime acid reflux. The reflux of acidic gastric contents into the esophagus is thought to initiate a vagally mediated, reflex type of bronchoconstriction. (Asthma may also aggravate GERD, because antiasthma medications that dilate the airways also relax muscle tone in the gastroesophageal sphincter and may increase acid reflux.) Additional precipitants may include allergens (eg, pollens, molds, others), airway irritants and pollutants (eg, chemical fumes, cigarette smoke, automobile exhaust), cold air, and exercise.
Acute episodes of asthma may last minutes to hours. Bronchoconstriction (also called bronchospasm) involves strong muscle contractions that narrow the airways. Airway smooth muscle extends from the trachea through the bronchioles. It is wrapped around the airways in a spiral pattern, and contraction causes a sphincter-type of action that can completely occlude the airway lumen. Bronchoconstriction is aggravated by inflammation, mucosal edema, and excessive mucus and may be precipitated by the numerous stimuli described above.
When lung tissues are exposed to causative stimuli, mast cells release substances that cause bronchoconstriction and inflammation. Mast cells are found throughout the body in connective tissues and are abundant in tissues surrounding capillaries in the lungs. When sensitized mast cells in the lungs or eosinophils in the blood are exposed to allergens or irritants, multiple cytokines and other chemical mediators (eg, acetylcholine, cyclic guanosine monophosphate [GMP], histamine, interleukins, leukotrienes, prostaglandins, and serotonin) are synthesized and released. These chemicals act directly on target tissues of the airways, causing smooth muscle constriction, increased capillary permeability and fluid leakage, and changes in the mucus-secreting properties of the airway epithelium.
Bronchoconstrictive substances are antagonized by cyclic adenosine monophosphate (cyclic AMP). Cyclic AMP is an intracellular substance that initiates various intracellular activities, depending on the type of cell. In lung cells, cyclic AMP inhibits release of bronchoconstrictive substances and thus indirectly promotes bronchodilation. In mild to moderate asthma, bronchoconstriction is usually recurrent and reversible, either spontaneously or with drug therapy. In advanced or severe asthma, airway obstruction becomes less reversible and worsens because chronically inflamed airways undergo structural changes (eg, fibrosis, enlarged smooth muscle cells, and enlarged mucous glands), called “airway remodeling,” that inhibit their function.
DRUG THERAPY
Two major groups of drugs used to treat asthma, acute and chronic bronchitis, and emphysema are bronchodilators and anti-inflammatory drugs. Bronchodilators are used to prevent and treat bronchoconstriction; anti-inflammatory drugs are used to prevent and treat inflammation of the airways. Reducing inflammation also reduces bronchoconstriction by decreasing mucosal edema and mucus secretions that narrow airways and by decreasing airway hyperreactivity to various stimuli.
BRONCHODILATORS
Beta 2 Agonists
Beta 2 Agonists are a group of medications formulated to act on special receptors called beta-2 receptors, located predominantly on smooth muscle and mucous membrane in the lungs and smaller airways. They also act on cells called mast cells to prevent release of substances which play a role in asthma attacks. Additionally, they may help clear mucous from the lungs. As the airways dilate, any mucous present can move more freely and can be coughed out of the airways.
There are two categories of beta 2 agonists used in asthma:
Short/ Intermediate acting agents:
(Salbutamol, Isoproterenol, Albuterol, Metaproterenol and Terbutaline) – these are usually administered via devices, to deliver the medication straight to the lungs (ie puffers, nebulisers, inhaler). They act within 30 minutes and last for about 4-6 hours. They are often used as needed, to control symptoms. They are quick acting agents, relieving asthma symptoms by opening the airways.
They remain first line agents for relief of acute symptoms and can be effective for both exercise and allergens induced asthma. Care must be taken to ensure that beta agonists are combined with other types of treatment to provide the best control of disease and symptoms, in the long run. They only act acutely and have no sustained actions on other factors involved in diseases such as airways inflammation, oedema and mucous secretion. Increasing usage of beta agonists is a sign of unstable asthma, that needs to be better controlled.
Longer acting agents:
(Salmeterol and Formoterol) – these are usually taken via the inhaled route, through the nose and mouth and last for about 12 hours. These medications are best taken on a regular basis, to provide the best control of your symptoms and can be used in conjunction with glucocorticoids to provide additional control.
You can take beta agonists via different delivery systems, ranging from metered dose inhalers, nebulised solutions, oral liquids and tablets to dry powder inhalers. The route of delivery of the medication can play a role in determining how effective it is in treating your symptoms. It has been suggested that bronchodilator medications taken through the mouth or given as an injection into the veins is more effective than inhaled routes of delivery because this allows bypassing of mucous plugs that may block the airways. However, there is an increased risk of side effects associated with these modes of delivery.
There have been clinical studies performed which compare beta agonists given by two different routes – nebulised (inhaled) and intravenously (through the veins). Some earlier studies suggested advantages with giving medications through the veins, but subsequent studies with medications such as terbutaline and albuterol have demonstrated equivalent or superior effects on lung function using the nebulized (inhalation) route.
Another study involving 15 trials and 584 patients compared the outcomes achieved with the use of beta agonist therapy via the veins, for acute asthma. Intravenous therapy was not associated with improved outcomes in the study population or any identified subgroup.
Epinephrine may be injected subcutaneously in an acute attack of bronchoconstriction, with therapeutic effects in approximately 5 minutes and lasting for approximately 4 hours. However, an inhaled selective beta2 agonist is the drug of choice in this situation. Epinephrine is also available without prescription in a pressurized aerosol form (eg, Primatene).
Almost all over-the-counter aerosol products promoted for use in asthma contain epinephrine. These products are often abused and may delay the client from seeking medical attention. Clients should be cautioned that excessive use may produce hazardous cardiac stimulation and other adverse effects.
Albuterol, bitolterol, levalbuterol, and pirbuterol are short-acting beta2-adrenergic agonists used for prevention and treatment of bronchoconstriction. These drugs act more selectively on beta2 receptors and cause less cardiac stimulation than epinephrine. Most often taken by inhalation, they are also the most effective bronchodilators and the treatment of first choice to relieve acute asthma. Because the drugs can be effectively delivered by aerosol or nebulization, even to young children and patients on mechanical ventilation, there is seldom a need to give epinephrine or other nonselective adrenergic drugs by injection.
The beta2 agonists are usually self-administered by metereddose inhalers (MDIs). Although most drug references still list a regular dosing schedule (eg, every 4 to 6 hours), asthma experts recommend that the drugs be used wheeeded (eg, to treat acute dyspnea or prevent dyspnea during exercise). If these drugs are overused, they lose their bronchodilating effects because the beta2-adrenergic receptors become unresponsive to stimulation. This tolerance does not occur with the long-acting beta2 agonists.
Formoterol and salmeterol are long-acting beta2-adrenergic agonists used only for prophylaxis of acute bronchoconstriction. They are not effective in acute attacks because they have a slower onset of action than the shortacting drugs (up to 20 minutes for salmeterol). Effects last exercise-induced asthma. In high doses, metaproterenol loses some of its selectivity and may cause cardiac and central nervous system (CNS) stimulation.
Terbutaline is a relatively selective beta2-adrenergic agonist that is a long-acting bronchodilator. When given subcutaneously, terbutaline loses its selectivity and has little advantage over epinephrine. Muscle tremor is the most frequent side effect with this agent.
The use of sympathomimetic agents by inhalation at first raised fears about possible cardiac arrhythmias and about hypoxemia acutely and tachyphylaxis or tolerance when given repeatedly. It is true that the vasodilating action of b2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2). This effect is usually small, however, and may occur with any bronchodilator drug; the significance of such an effect depends on the initial PaO2 of the patient. Administration of supplemental oxygen, routine in treatment of an acute severe attack of asthma, eliminates any concern over this effect. The other concern, that b-agonist treatment may cause lethal cardiac arrhythmias appears unsubstantiated. In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange effected by bronchodilator treatment.
The concept that b-agonist drugs cause worsening of clinical asthma by inducing tachyphylaxis to their own action remains unestablished. Most studies have shown only a small change in the bronchodilator response to b stimulation after prolonged treatment with b-agonist drugs, but some studies have shown a loss in the ability of b-agonist treatment to inhibit the response to subsequent challenge with exercise, methacholine, or antigen challenge (referred to as a loss of bronchoprotective action).
Fears that heavy use of b-agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations. Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids.
Although it is true that b2-adrenoceptor agonists appear to be safe and effective bronchodilators for most patients, there is some evidence that the risk of adverse effects from chronic treatment with long-acting b agonists may be greater for some individuals, possibly as a function of genetic variants for the b receptor. Two retrospective and one prospective study have shown differences between patients homozygous for glycine versus arginine at the B-16 locus of the b receptor. Among patients homozygous for arginine, a genotype found in 16% of the Caucasian population in the USA, but more commonly in African Americans, asthma control deteriorated with regular use of albuterol or salmeterol, whereas asthma control improved with this treatment among those homozygous for glycine at the same locus. These findings need to be replicated in larger studies, but it is tempting to speculate that a genetic variant may underlie the report of an increase in asthma mortality from regular use of a long-acting b agonist in studies involving very large numbers of patients.
Xanthines
Pharmacodynamics of Methylxanthines
The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects.
A. CENTRAL NERVOUS SYSTEM EFFECTS
In low and moderate doses, the methylxanthines¾especially caffeine¾cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages¾eg, 100 mg in a cup of coffee¾is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma. The larger doses necessary for more effective bronchodilation commonly cause nervousness and tremor in some patients. Very high doses, from accidental or suicidal overdose, cause medullary stimulation and convulsions and may lead to death.
B. CARDIOVASCULAR EFFECTS
The methylxanthines have positive chronotropic and inotropic effects. At low concentrations, these effects appear to result from inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release at nerve endings. The higher concentrations (> 10 umol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (> 100 umol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.
The clinical expression of these effects on cardiovascular function varies among individuals. Ordinary consumption of coffee and other methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. In large doses, these agents also relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.
Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. However, no evidence suggests that this therapy is superior to other approaches.
C. EFFECTS ON GASTROINTESTINAL TRACT
The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.
D. EFFECTS ON KIDNEY
The methylxanthines¾especially theophylline¾are weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful.
E. EFFECTS ON SMOOTH MUSCLE
The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, may limit the dose (see below). In addition to their effect on airway smooth muscle, these agents¾in sufficient concentration¾inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.
F. EFFECTS ON SKELETAL MUSCLE
The respiratory actions of the methylxanthines may not be confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD. This effect on diaphragmatic performance¾rather than an effect on the respiratory center¾may account for theophylline’s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.
There are three main active, naturally occurring methylxanthines – theophylline, theobromine and caffeine. Theophylline is the most commonly used xanthine in treatment of asthma, also used as aminophylline. Theophylline has a proven dilatory action on the airways, although it is less effective compared to the beta 2 adrenoceptor agonists. Several studies have shown that theophylline is both effective in relieving the acute attack and in the treatment of chronic asthma. Additional actions to dilating the airways seems to be implicated, as theophylline has effects on the later stages of asthma.
Xanthines are most commonly used in severe airways obstruction, including cases of acute asthma, and also in maintenance treatment of severe asthma and lung diseases such as bronchitis and empysema.
The exact mechanism by which xanthines produce it’s effects in asthmatic patients is still unclear. It is thought that they induce smooth muscle relaxation, via inhibition of a substance called phosphodiesterase. This allows an increase in cyclic AMP which acts to counteract the inflammatory effects that occur in the later stages of asthma.
Note that xanthines also have actions on other bodily systems including: the central nervous system, heart and major vessels, and kidney. These actions on other systems result in many of the side effects of the drugs. They have a stimulant effect on the central nervous system, resulting in increased alertness, tremor and nervousness. All the xanthines also exhibit a stimulant effect on the heart, causing dilation of blood vessels. They can also act on the kidney to increase urine output and flow.
These drugs are only effective if the cause of your symptoms is due to smooth muscle contraction and airways constriction.
Most xanthine medications are given orally, via slow release preparations. Aminophylline can also be given via the veins as a slow infusion, especially if you present in the emergency setting, with an acute, sustained asthma attack (also known as status asthmaticus).
Overall, theophylline is used as a second line drug in asthma therapy, often in addition to steroids and other anti-asthmatic medications in patients whose asthma is not adequately controlled by other bronchodilators.
Muscarinic Receptor Antagonists
The muscarinic receptor antagonists are a group of bronchodilators that includes medications such as ipratropium and oxitropium. The drug used most commonly in treatment of asthmatics is ipratropium.
There are sensory nerve endings present in the lining of our airways – when these are activated, they induce constriction and narrowing of the airways. Muscarinic receptor antagonists act to relax constriction of airways due to activation of these nerves by stimulation of the parasympathetic system. These medications have been shown to be particularly effective in allergic irritant asthma.
As their name suggests, muscarinic receptor antagonists act to block muscarinic receptors, but they do not discriminate between the different types. They can help decrease mucous secretion and may increase the lung’s ability to clear airway secretions.
Muscarinic receptor antagonists are given via inhaled delivery systems, (ie through the nose) because they are not well absorbed into the body’s circulation. Their peak effect occurs about 30 minutes after administration, lasting for about 3-5 hours. Often, these medications are used with the beta 2 adrenoceptor antagonists.
Ipatropium can also be used to dilate the airways in patients with chronic bronchitis and to treat spasm of the airways precipitated by beta 2 adrenoceptor antagonists. It has been shown to be as effective as inhaled beta 2 agonists in the treatment of stable lung disease. These medications are often employed in maintenance treatment of patients with lung disease such as bronchitis, emphysema, and severe asthma.
ANTI-INFLAMMATORY AGENTS
Corticosteroids
Corticosteroids are used in the treatment of acute and chronic asthma and other bronchoconstrictive disorders, in which they have two major actions. First, they suppress inflammation in the airways by inhibiting the following processes: movement of fluid and protein into tissues; migration and function of neutrophils and eosinophils; synthesis of histamine in mast cells; and production of proinflammatory substances (eg, prostaglandins, leukotrienes, several interleukins, and others). Beneficial effects of suppressing airway inflammation include decreased mucus secretion, decreased edema of airway mucosa, and repair of damaged epithelium, with subsequent reduction of airway reactivity. A second action is to increase the number and sensitivity of beta2-adrenergic receptors, which restores or increases the effectiveness of beta2-adrenergic bronchodilators. The number of beta2 receptors increases within approximately 4 hours, and improved responsiveness to beta2 agonists occurs within approximately 2 hours.
In acute, severe asthma, a systemic corticosteroid in relatively high doses is indicated in patients whose respiratory distress is not relieved by multiple doses of an inhaled beta2 agonist (eg, every 20 minutes for 3 to 4 doses). The corticosteroid may be given IV or orally, and IV administration offers no therapeutic advantage over oral administration. Once the drug is started, pulmonary function usually improves in 6 to 8 hours. Most patients achieve substantial benefit within 48 to 72 hours and the drug is usually continued for 7 to 10 days. Multiple doses are usually given because studies indicate that maintaining the drug concentration at steroid receptor sites in the lung is more effective than high single doses.
High single or pulse doses do not increase therapeutic effects; they may increase risks of developing myopathy and other adverse effects, however. In some infants and young children with acute, severe asthma, oral prednisone for 3 to 10 days has relieved symptoms and prevented hospitalization.
In chronic asthma, a corticosteroid is usually taken by inhalation, on a daily schedule. It is often given concomitantly with one or more bronchodilators and may be given with another anti-inflammatory drug such as a leukotriene modifier or a mast cell stabilizer. In some instances, the other drugs allow smaller doses of the corticosteroid. For acute flare-ups of symptoms during treatment of chronic asthma, a systemic corticosteroid may be needed temporarily to regain control.
In early stages of the progressive disease, patients with COPD are unlikely to need corticosteroid therapy. In later stages, however, they usually need periodic short-course therapy for episodes of respiratory distress. Wheeeded, the corticosteroid is given orally or parenterally because effectiveness of inhaled corticosteroids has not been established in COPD. In end-stage COPD, patients often become “steroiddependent” and require daily doses because any attempt to reduce dosage or stop the drug results in respiratory distress. Such patients experience numerous serious adverse effects of prolonged systemic corticosteroid therapy.
Corticosteroids should be used with caution in clients with peptic ulcer disease, inflammatory bowel disease, hypertension, ongestive heart failure, and thromboembolic disorders. However, they cause fewer and less severe adverse effects when taken in short courses or by inhalation than when taken systemically for long periods of time.
Beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone are topical corticosteroids for inhalation. Topical administration minimizes systemic absorption and adverse effects. These preparations may substitute for or allow reduced dosage of systemic corticosteroids. In people with asthma who are taking an oral corticosteroid, the oral dosage is reduced slowly (over weeks to months) when an inhaled corticosteroid is added. The goal is to give the lowest oral dose necessary to control symptoms. Beclomethasone, flunisolide, and fluticasone also are available iasal solutions for treatment of allergic rhinitis, which may play a role in bronchoconstriction. Because systemic absorption occurs in clients using inhaled corticosteroids (about 20% of a dose), high doses should be reserved for those otherwise requiring oral corticosteroids.
Hydrocortisone, prednisone, and methylprednisolone are given to clients who require systemic corticosteroids. Prednisone is given orally; hydrocortisone and methylprednisolone may be given IV to patients who are unable to take an oral medication.
Leukotriene Modifiers
Leukotrienes are strong chemical mediators of bronchoconstriction and inflammation, the major pathologic features of asthma. They can cause sustained constriction of bronchioles and immediate hypersensitivity reactions. They also increase
mucus secretion and mucosal edema in the respiratory tract. Leukotrienes are formed by the lipoxygenase pathway of arachidonic acid metabolism (Fig. 47–1) in response to cellular injury. They are designated by LT, the letter B, C, D, or E, and the number of chemical bonds in their structure (eg, LTB4, LTC4, and LTE4, also called slow releasing substances of anaphylaxis or SRS-A, because they are released more slowly than histamine).
Leukotriene modifier drugs were developed to counteract the effects of leukotrienes and are indicated for long-term treatment of asthma in adults and children. The drugs help to prevent acute asthma attacks induced by allergens, exercise, cold air, hyperventilation, irritants, and aspirin or NSAIDs.
They are not effective in relieving acute attacks. However, they may be continued concurrently with other drugs during acute episodes.
The leukotriene modifiers include three agents with two different mechanisms of action. Zileuton inhibits lipoxygenase and thereby reduces formation of leukotrienes; montelukast and zafirlukast are leukotriene receptor antagonists. Zileuton is used infrequently because it requires multiple daily dosing, may cause hepatotoxicity, and may inhibit the metabolism of drugs metabolized by the cytochrome P450 3A4 enzymes. Zafirlukast and montelukast improve symptoms and pulmonary function tests (PFTs), decrease nighttime symptoms, and decrease the use of beta2 agonist drugs.
They are effective with oral administration, can be taken once or twice a day, can be used with bronchodilators and corticosteroids, and elicit a high degree of patient adherence and satisfaction. However, they are less effective than low doses of inhaled corticosteroids. Montelukast and zafirlukast are well absorbed with oral administration. They are metabolized in the liver by the cytochrome P450 enzyme system and may interact with other drugs metabolized by this system. Most metabolites are excreted in the feces. Zafirlukast is excreted in breast milk and should not be taken during lactation. The most common adverse effects reported in clinical trials were headache, nausea, diarrhea, and infection. Zileuton is well absorbed, highly bound to serum albumin (93%), and metabolized by the cytochrome P450 liver enzymes; metabolites are excreted mainly in urine. It is contraindicated in clients with active liver disease or substantially levated liver enzymes (three times the upper limit of normal values). When used, hepatic aminotransferase enzymes should be monitored during therapy and the drug should be discontinued if enzyme levels reach five times the normal values or if symptoms of liver dysfunction develop. Elevation of liver enzymes was the most serious adverse effect during clinical trials; other adverse effects include headache, pain, and nausea. In addition, zileuton increases serum concentrations of propranolol, theophylline, and warfarin.
Mast Cell Stabilizers
Cromolyn and nedocromil stabilize mast cells and prevent the release of bronchoconstrictive and inflammatory substances when mast cells are confronted with allergens and other stimuli. The drugs are indicated only for prophylaxis of acute asthma attacks in clients with chronic asthma; they are not effective in acute bronchospasm or status asthmaticus and should not be used in these conditions. Use of one of these drugs may allow reduced dosage of bronchodilators and corticosteroids.
The drugs are taken by inhalation. Cromolyn is available in a metered-dose aerosol and a solution for use with a poweroperated nebulizer. A nasal solution is also available for prevention and treatment of allergic rhinitis. Nedocromil is available in a metered-dose aerosol. Mast cell stabilizers are contraindicated in clients who are hypersensitive to the drugs. They should be used with caution in clients with impaired renal or hepatic function. Also, the propellants in the aerosols may aggravate coronary artery disease or dysrhythmias.
Side effects
Some patients have a dry or irritated throat or a dry mouth after using bronchodilators. To help prevent these problems, gargle and rinse the mouth or take a sip of water after each dose.
The most common side effects are nervousness or restlessness and trembling. These problems usually go away as the body adjusts to the drug and do not require medical treatment.
Less common side effects, such as bad taste in the mouth, coughing, dizziness or lightheadedness, drowsiness, headache, sweating, fast or pounding heartbeat, muscle cramps or twitches, nausea, vomiting, diarrhea, sleep problems and weakness also may occur and do not need medical attention unless they do not go away or they interfere with normal activities.
More serious side effects are not common, but may occur. If any of the following side effects occur, check with the physician who prescribed the medicine as soon as possible:
· Chest pain or discomfort
· Irregular or fluttery heartbeat
· Unusual bruising
· Hives or rash
· Swelling
· Wheezing or other breathing problems
· Numbness in the hands or feet
· Blurred vision.
Other side effects are possible. Anyone who has unusual symptoms after using a bronchodilator should get in touch with his or her physician.
OTHER DRUGS IN THE TREATMENT OF ASTHMA
Anti-IgE Monoclonal Antibodies
An entirely new approach to the treatment of asthma exploits advances in molecular biology to target IgE antibody. From a collection of monoclonal antibodies raised in mice against IgE antibody itself, a monoclonal antibody was selected that appeared to be targeted against the portion of IgE that binds to its receptors (FCe-R1 and FCe-R2 receptors) on mast cells and other inflammatory cells. Omalizumab (an anti-IgE monoclonal antibody) inhibits the binding of IgE to mast cells but does not activate IgE already bound to these cells and thus does not provoke mast cell degranulation. It may also inhibit IgE synthesis by B lymphocytes. The murine antibody has been genetically humanized by replacing all but a small fraction of its amino acids with those found in human proteins, and it does not appear to cause sensitization when given to human subjects.
Studies of omalizumab in asthmatic volunteers showed that its administration over 10 weeks lowered plasma IgE to undetectable levels and significantly reduced the magnitude of both the early and the late bronchospastic responses to antigen challenge. Clinical trials have shown that repeated intravenous or subcutaneous injection of anti-IgE MAb lessens asthma severity and reduces the corticosteroid requirement in patients with moderate to severe disease, especially those with a clear environmental antigen precipitating factor, and improves nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis. Omalizumab’s most important effect is reduction of the frequency and severity of asthma exacerbations, even while enabling a reduction in corticosteroid requirements. Combined analysis of several clinical trials has shown that the patients most likely to respond are, fortunately, those with the greatest need, ie, patients with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmonary function. Similarly, the exacerbations most prevented are the ones most important to prevent: Omalizumab treatment reduced exacerbations requiring hospitalization by 88%. These benefits justify the high cost of this treatment in selected individuals with severe disease characterized by frequent exacerbations.
The rapid advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies targeting different sites in the immune cascade. These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens. There is evidence that asthma may be aggravated¾or even caused¾by chronic airway infection with Chlamydia pneumoniae or Mycoplasma pneumoniae. This may explain the reports of benefit from treatment with macrolide antibiotics and, if confirmed, would stimulate the development of new diagnostic methods and antimicrobial therapies.
Asthma is best thought of as a disease in two time domains. In the present domain, it is important for the distress it causes¾cough, nocturnal awakenings, and shortness of breath that interferes with the ability to exercise or to pursue desired activities. For mild asthma, occasional inhalation of a bronchodilator may be all that is needed. For more severe asthma, treatment with a long-term controller, like an inhaled corticosteroid, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations, or of progressive loss of pulmonary function. A patient’s satisfaction with his or her ability to control symptoms and maintain function by frequent use of an inhaled b2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled b agonist per month is a marker of increased risk of asthma fatality.
The challenges of assessing severity and adjusting therapy for these two domains of asthma are different. For relief of distress in the present domain, the key information can be obtained by asking specific questions about the frequency and severity of symptoms, the frequency of use of an inhaled b2 agonist for relief of symptoms, the frequency of nocturnal awakenings, and the ability to exercise. Estimating the risk for future exacerbations is more difficult. In general, patients with poorly controlled symptoms in the present have a heightened risk of exacerbations in the future, but some patients seem unaware of the severity of their underlying airflow obstruction (sometimes described as “poor perceivers”) and can be identified only by measurement of pulmonary function, as by spirometry. Reductions in the FEV1 correlate with heightened risk of attacks of asthma in the future. Other possible markers of heightened risk are unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), extreme bronchial reactivity, or high numbers of eosinophils in sputum or of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against exacerbations.
Bronchodilators, such as inhaled albuterol, are rapidly effective, safe, and inexpensive. Patients with only occasional symptoms of asthma require no more than an inhaled b2-receptor agonist taken on an as-needed basis. If symptoms require this “rescue” therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% predicted, additional treatment is needed. The treatment first recommended is a low dose of an inhaled corticosteroid, although treatment with a leukotriene receptor antagonist or with cromolyn may be used. Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled despite the combination of regular treatment with an inhaled anti-inflammatory agent and as-needed use of a b2 agonist. If the addition of theophylline fails to improve symptoms or if adverse effects become bothersome, it is important to check the plasma level of theophylline to be sure it is in the therapeutic range (10-20 mg/L).
An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is lower than in patients with severe asthma, it is not zero. All patients with asthma should be instructed in a simple action plan for severe, frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour. If they do not note clear improvement after the first four puffs, they should take the additional treatments while on their way to an Emergency Department or some other higher level of care.
Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. When adequate doses are given, their effect on baseline airway resistance is nearly as great as that of the sympathomimetic drugs. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in patients with severe airflow obstruction who present for emergency care. Antimuscarinic agents appear to be of greater value in COPD¾perhaps more so than in asthma. They are also useful as alternative therapies for patients intolerant of b2-adrenoceptor agonists.
Although it was predicted that muscarinic antagonists would dry airway secretions and interfere with mucociliary clearance, direct measurements of fluid volume secretion from single airway submucosal glands in animals show that atropine decreases baseline secretory rates only slightly. The drugs do, however, inhibit the increase in mucus secretion caused by vagal stimulation. No cases of inspissation of mucus have been reported following administration of these drugs.
If asthmatic symptoms occur frequently or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 < 50% predicted), initial treatment with a combination of inhaled and oral corticosteroid (eg, 30 mg/d of prednisone for 3 weeks) treatment is appropriate. Once clinical improvement is noted, usually after 7-10 days, the oral dose should be discontinued or reduced to the minimum necessary to control symptoms.
An issue for inhaled corticosteroid treatment is patient compliance. Analysis of prescription renewals shows that corticosteroids are taken regularly by a minority of patients. This may be a function of a general “steroid phobia” fostered by emphasis in the lay press over the hazards of long-term oral corticosteroid therapy and by ignorance over the difference between corticosteroids and anabolic steroids, taken to enhance muscle strength by now-infamous athletes. This fear of corticosteroid toxicity makes it hard to persuade patients whose symptoms have improved after starting the treatment that they should continue it for protection against attacks. This context accounts for the interest in a recent report that instructing patients with mild but persistent asthma to initiate inhaled corticosteroid therapy only when their symptoms worsened was as effective in maintaining pulmonary function and preventing attacks as taking it twice each day.
In patients with more severe asthma, whose symptoms are inadequately controlled by a standard dose of an inhaled corticosteroid, two options may be considered: to double the dose of inhaled corticosteroid or to add a long-acting inhaled b2-receptor agonist (salmeterol or formoterol). Many studies have shown this combination therapy to be more effective than doubling the dose of the inhaled corticosteroid, but the FDA has issued a warning that the use of a long-acting b agonist is associated with a very small but statistically significant increase in the risk of death or near death from an asthma attack, especially in African Americans. This warning has not so far had much effect on prescriptions for a fixed-dose combination of inhaled fluticasone (a corticosteroid) and salmeterol (a long-acting b agonist), probably because their combination in a single inhaler offers several advantages. Combination inhalers are convenient; they ensure that the long-acting b agonist will not be taken as monotherapy (knowot to protect against attacks); and they produce prompt, sustained improvements in clinical symptoms and pulmonary function and reduce the frequency of exacerbations requiring oral corticosteroid treatment. In patients prescribed such combination treatment, it is important to provide explicit instructions that a standard, short-acting inhaled b2 agonist, such as albuterol, be used as needed for relief of acute symptoms.
CROMOLYN & NEDOCROMIL; LEUKOTRIENE ANTAGONISTS
Cromolyn or nedocromil by inhalation, or a leukotriene-receptor antagonist as an oral tablet, may be considered as alternatives to inhaled corticosteroid treatment in patients with symptoms occurring more than twice a week or who are wakened from sleep by asthma more than twice a month. Neither treatment is as effective as even a low dose of an inhaled corticosteroid, but both prevent the issue of “steroid phobia” described above.
Cromolyn and nedocromil may also be useful in patients whose symptoms occur seasonally or after clear-cut inciting stimuli such as exercise or exposure to animal danders or irritants. In patients whose symptoms are continuous or occur without an obvious inciting stimulus, the value of these drugs can be established only with a therapeutic trial of inhaled drug four times a day for 4 weeks. If the patient responds to this therapy, the dose can then be optimized.
Treatment with a leukotriene-receptor antagonist, particularly montelukast, is widely prescribed, especially by primary care providers. Taken orally, leukotriene-receptor antagonists are easy to use and appear to be taken more regularly than inhaled corticosteroids. They are rarely associated with troublesome side effects. Maintenance therapy with a leukotriene antagonist or with cromolyn or nedocromil appears to be roughly as effective as maintenance therapy with theophylline. Because of concerns over the possible long-term toxicity of systemic absorption of inhaled corticosteroids, this maintenance therapy has become widely used for treating children in the USA.
Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting b-agonist combination treatment (eg, fluticasone 500 mcg plus salmeterol 50 mcg inhaled twice daily). This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice weekly subcutaneous injection.
OTHER ANTI-INFLAMMATORY THERAPIES
Some reports suggest that agents commonly used to treat rheumatoid arthritis may also be used to treat patients with chronic steroid-dependent asthma. The development of an alternative treatment is important, because chronic treatment with oral corticosteroids may cause osteoporosis, cataracts, glucose intolerance, worsening of hypertension, and cushingoid changes in appearance. Initial studies suggested that oral methotrexate or gold salt injections were beneficial in prednisone-dependent asthmatics, but subsequent studies did not confirm this promise. In contrast, the benefit from treatment with cyclosporine seems real. However, this drug’s great toxicity makes this finding only a source of hope that other immunomodulatory therapies will ultimately be developed for the small proportion of patients whose asthma can be managed only with high oral doses of prednisone. An immunomodulatory therapy recently reported to improve asthma is injection of etanercept, a TNF-a antagonist used for treatment of ankylosing spondylitis and severe rheumatoid arthritis.
The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a b2-receptor agonist is as effective as subcutaneous injection of epinephrine. Both of these treatments are more effective than intravenous administration of aminophylline (a soluble salt of theophylline). Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration. General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes.
The high prevalence of asthma in the developed world and its rapid increases in the developing world call for a strategy for primary prevention. Strict antigen avoidance during infancy, once thought to be sensible, has now been shown to be ineffective. In fact, growing up in a household where cats and dogs are kept as pets may protect against developing asthma. The best hope seems to lie in understanding the importance of microbial exposures during infancy in shaping a balanced immune response, and one study showing that feeding Lactobacillus caseii to infants born to allergic parents reduced the rate of allergic dermatitis at age 2 years offers reason for hope.
Mycobacteria are intrinsically resistant to most antibiotics. Because they grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter.
Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis. Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy.
In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they provide additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. The prevalence of isoniazid resistance among US clinical isolates is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (ie, multiple drug resistance) is about 3%.
Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is small (MW 137) and freely soluble in water.
In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms.
Mechanism of Action & Basis of Resistance
Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell. Resistance to isoniazid is associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of the katG gene; promoter mutations resulting in overexpression of ahpC, a putative virulence gene involved in protection of the cell from oxidative stress; and mutations in kasA. Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide.
Drug-resistant mutants are normally present in susceptible mycobacterial populations at about 1 bacillus in 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected out if isoniazid or any other drug is given as a single agent. The use of two independently acting drugs in combination is much more effective. The probability that a bacillus is resistant to both drugs is approximately 1 in 106 ´ 106, or 1 in 1012, several orders of magnitude greater than the number of infecting organisms. Thus, at least two (or more in certain cases) active agents should always be used to treat active tuberculosis to prevent emergence of resistance during therapy.
Isoniazid is readily absorbed from the gastrointestinal tract. A 300-mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3-5 mcg/mL within 1-2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations.
Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined. The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption.
Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. The dose need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency (isoniazid is contraindicated if it is the cause of the hepatitis) and should be guided by serum concentrations if a reduction in dose is contemplated.
The usual dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin 600 mg). Pyridoxine, 25-50 mg/d, is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage.
Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.
Adverse Reactions
The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.
A. IMMUNOLOGIC REACTIONS
Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.
B. DIRECT TOXICITY
Isoniazid-induced hepatitis is the most common major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal), which do not require cessation of the drug and which are seen in 10-20% of patients, who usually are asymptomatic. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those aged 21-35, 1.2% of those aged 36-50, and 2.3% for those aged 50 and above. The risk of hepatitis is greater in alcoholics and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug.
Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose. It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort. Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity.
RIFAMPIN
Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 106 and are rapidly selected out if rifampin is used as a single drug, especially if there is active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine.
Antimycobacterial Activity, Resistance, & Pharmacokinetics
Rifampin binds to the b subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the b subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.
Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5-7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.
A. MYCOBACTERIAL INFECTIONS
Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.
B. OTHER INDICATIONS
Rifampin has other uses. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis.
Adverse Reactions
Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors, contraceptives, and a host of others. Administration of rifampin results in significantly lower serum levels of these drugs.
ETHAMBUTOL
Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer, dispensed as the dihydrochloride salt.
Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1-5 mcg/mL. Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene.
Ethambutol is well absorbed from the gut. After ingestion of 25 mg/kg, a blood level peak of 2-5 mcg/mL is reached in 2-4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. Ethambutol crosses the blood-brain barrier only if the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation.
As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs.
Ethambutol hydrochloride, 15-25 mg/kg, is usually given as a single daily dose in combination with isoniazid or rifampin. The higher dose is recommended for treatment of tuberculous meningitis. The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used.
Adverse Reactions
Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness. This dose-related side effect is more likely to occur at doses of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.
PYRAZINAMIDE
Pyrazinamide (PZA) is a relative of nicotinamide, stable, and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes.
Pyrazinamide is converted to pyrazinoic acid¾the active form of the drug¾by mycobacterial pyrazinamidase, which is encoded by pncA. The drug target and mechanism of action are unknown. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of pyrazinamide to its active form.
Clinical Use
Serum concentrations of 30-50 mcg/mL at 1-2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8-11 hours. The parent compound is metabolized by the liver, but metabolites are renally cleared; therefore, pyrazinamide should be administered at 25-35 mg/kg three times weekly (not daily) in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min. In patients with normal renal function, a dose of 40-50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens. Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6-month) regimens as a “sterilizing” agent active against residual intracellular organisms that may cause relapse. Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs.
Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis.
The typical adult dose is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dose is 15 mg/kg two or three times a week. Most tubercle bacilli are inhibited by streptomycin, 1-10 mcg/mL, in vitro. Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10-100 mcg/mL. Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or the rrs gene encoding 16S ribosomal rRNA, which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges.
Streptomycin sulfate is used when an injectable drug is needed or desirable, principally in individuals with severe, possibly life-threatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20-40 mg/kg/d, not to exceed 1-1.5 g for children) for several weeks, followed by 1-1.5 g two or three times weekly for several months. Serum concentrations of approximately 40 mcg/mL are achieved 30-60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given in combination to prevent emergence of resistance.
Adverse Reactions
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common side effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function. Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible.
ALTERNATIVE SECOND-LINE DRUGS FOR TUBERCULOSIS
The alternative drugs listed below are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; (3) in case of serious treatment-limiting adverse drug reactions; and (4) when expert guidance is available to deal with the toxic effects. For many of the second-line drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established.
Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids. It is poorly water-soluble and available only in oral form. It is metabolized by the liver.
Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 20 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum.
Ethionamide is administered at an initial dose of 250 mg once daily, which is increased in 250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The 1 g/d dosage, although theoretically desirable, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur, and one often must settle for a total daily dose of 500-750 mg. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine.
Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be low-level cross-resistance between isoniazid and ethionamide.
Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis.
Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis. Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may occur.
Dosing of capreomycin is the same as that of streptomycin. Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule.
Cycloserine
Concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min.
The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions. Pyridoxine 150 mg/d should be given with cycloserine because this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses. Side effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2-4 hours after dosing. The recommended range of peak concentrations is 20-40 mcg/mL.
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis. It is structurally similar to p-aminobenzoic aid (PABA) and to the sulfonamides.
Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1-5 mcg/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 mcg/mL or more after a 4-g oral dose. The dosage is 8-12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.
Aminosalicylic acid is used infrequently now because other oral drugs are better tolerated. Gastrointestinal symptoms are common and may be diminished by giving the drug with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3-8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently.
Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete.
The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis. Prevalence of amikacin-resistant strains is low (less than 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30-50 mcg/mL are achieved 30-60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosages are the same as that for streptomycin.
In addition to their activity against many gram-positive and gram-negative bacteria, ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis by weight in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria.
Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents. The standard dosage of ciprofloxacin is 750 mg orally twice a day. The dosage of levofloxacin is 500-750 mg once a day. The dosage of moxifloxacin is 400 mg once a day.
Linezolid inhibits strains of M tuberculosis in vitro at concentrations of 4 to 8 mcg/mL. It achieves good intracellular concentrations, and it is active in murine models of tuberculosis. Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains. Conversion of sputum cultures to negative was associated with linezolid use in these cases, and some may have been cured. Significant and at times treatment-limiting adverse effects, including bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis. A 600-mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections) seems to be sufficient and may limit the occurrence of these adverse effects. Although linezolid may eventually prove to be an important new agent for treatment of tuberculosis, at this point it should be considered a drug of last resort for infection caused by multidrug-resistant strains that also are resistant to several other first- and second-line agents.
Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)¾drugs that also are cytochrome P450 substrates.
The usual dose of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dose should be reduced to 150 mg/d. If efavirenz (also a P450 inducer) is used, the recommended dose of rifabutin is 450 mg/d.
Rifabutin is effective in prevention and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4 counts below 50/uL. It is also effective for preventive therapy of tuberculosis, either alone in a 3-4 month regimen or with pyrazinamide in a 2-month regimen.
Rifapentine is an analog of rifampin. It is active against both M tuberculosis and M avium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine 600 mg (10 mg/kg) once weekly is indicated for treatment of tuberculosis caused by rifampin-susceptible strains during the continuation phase only (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative). Rifapentine should not be used to treat HIV-infected patients because of an unacceptably high relapse rate with rifampin-resistant organisms.
DRUGS ACTIVE AGAINST ATYPICAL MYCOBACTERIA
About 10% of mycobacterial infections seen in clinical practice in the USA are caused not by M tuberculosis or M tuberculosis complex organisms, but by nontuberculous or so-called “atypical” mycobacteria. These organisms have distinctive laboratory characteristics, are present in the environment, and are not communicable from person to person. As a rule, these mycobacterial species are less susceptible than M tuberculosis to antituberculous drugs. On the other hand, agents such as erythromycin, sulfonamides, or tetracycline, which are not active against M tuberculosis, may be effective for infections caused by atypical strains. Emergence of resistance during therapy is also a problem with these mycobacterial species, and active infection should be treated with combinations of drugs. M kansasii is susceptible to rifampin and ethambutol, partially resistant to isoniazid, and completely resistant to pyrazinamide. A three-drug combination of isoniazid, rifampin, and ethambutol is the conventional treatment for M kansasii infection.
M avium complex, which includes both M avium and M intracellulare, is an important and common cause of disseminated disease in late stages of AIDS (CD4 counts < 50/uL). M avium complex is much less susceptible than M tuberculosis to most antituberculous drugs. Combinations of agents are required to suppress the disease. Azithromycin, 500 mg once daily, or clarithromycin, 500 mg twice daily, plus ethambutol, 15-25 mg/kg/d, is an effective and well-tolerated regimen for treatment of disseminated disease. Some authorities recommend use of a third agent, such as ciprofloxacin 750 mg twice daily or rifabutin, 300 mg once daily. Rifabutin in a single daily dose of 300 mg has been shown to reduce the incidence of M avium complex bacteremia in AIDS patients with CD4 less than 100/uL. Clarithromycin also effectively prevents MAC bacteremia in AIDS patients, but if breakthrough bacteremia occurs, the isolate often is resistant to both clarithromycin and azithromycin, precluding the use of the most effective drugs for treatment.
PREPARATIONS AVAILABLE
SYMPATHOMIMETICS USED IN ASTHMA
Albuterol (generic, Proventil, Ventolin)
Inhalant: 90 mcg/puff aerosol; 0.083, 0.5, 0.63% solution for nebulization
Oral: 2, 4 mg tablets; 2 mg/5 mL syrup
Oral sustained-release: 4, 8 mg tablets
Albuterol/Ipratropium (Combivent, DuoNeb)
Inhalant: 103 mcg albuterol + 18 mcg ipratropium/ puff; 3 mg albuterol + 0.5 mg ipratropium/3 mL solution for nebulization
Bitolterol (Tornalate)
Inhalant: 0.2% solution for nebulization
Ephedrine (generic)
Oral: 25 mg capsules
Parenteral: 50 mg/mL for injection
Epinephrine (generic, Adrenalin)
Inhalant: 1, 10 mg/mL for nebulization; 0.22 mg/spray epinephrine base aerosol
Parenteral: 1:10,000 (0.1 mg/mL), 1:1000 (1 mg/mL)
Formoterol (Foradil)
Inhalant: 12 mcg/unit inhalant powder
Isoetharine (generic)
Inhalant: 1% solution for nebulization
Isoproterenol (generic, Isuprel)
Inhalant: 0.5, 1% for nebulization; 80, 131 mcg/puff aerosols
Parenteral: 0.02, 0.2 mg/mL for injection
Levalbuterol (Xenopex)
Inhalant: 0.31, 0.63, 1.25 mg/3 mL solution
Metaproterenol (Alupent, generic)
Inhalant: 0.65 mg/puff aerosol in 7, 14 g containers; 0.4, 0.6, 5% for nebulization
Pirbuterol (Maxair)
Inhalant: 0.2 mg/puff aerosol in 80 and 300 dose containers
Salmeterol (Serevent)
Inhalant aerosol: 25 mcg salmeterol base/puff in 60 and 120 dose containers
Inhalant powder: 50 mcg/unit
Salmeterol/Fluticasone (Advair Diskus)
Inhalant: 100, 250, 500 mcg fluticasone + 50 mcg salmeterol/unit
Terbutaline (generic, Brethine)
Oral: 2.5, 5 mg tablets
Parenteral: 1 mg/mL for injection
AEROSOL CORTICOSTEROIDS
Beclomethasone (QVAR)
Aerosol: 40, 80 mcg/puff in 100 dose containers
Budesonide (Pulmicort)
Aerosol powder (Turbuhaler): 160 mcg/activation
Inhalation suspension (Respules): 0.25, 0.5 mg/2 mL
Flunisolide (AeroBid, Aerospan)
Aerosol: 80, 250 mcg/puff in 80, 100, and 120 dose containers
Fluticasone (Flovent)
Aerosol: 44, 110, and 220 mcg/puff in 120 dose container; powder, 50, 100, 250 mcg/activation
Fluticasone/Salmeterol (Advair Diskus)
Inhalant: 100, 250, 500 mcg fluticasone + 50 mcg salmeterol/unit
Mometasone (Asmanex Twisthaler)
Inhalant: 220 mcg/actuation in 14, 30, 60, 120 dose units
Triamcinolone (Azmacort)
Aerosol: 100 mcg/puff in 240 dose container
LEUKOTRIENE INHIBITORS
Montelukast (Singulair)
Oral: 10 mg tablets; 4, 5 mg chewable tablets; 4 mg/packet granules
Zafirlukast (Accolate)
Oral: 10, 20 mg tablets
Zileuton (Zyflo)
Oral: 600 mg tablets
CROMOLYN SODIUM & NEDOCROMIL SODIUM
Cromolyn sodium
Pulmonary aerosol (generic, Intal): 800 mcg/puff in 200 dose container; 20 mg/2 mL for nebulization (for asthma)
Nasal aerosol (Nasalcrom): 5.2 mg/puff (for hay fever)
Oral (Gastrocrom): 100 mg/5 mL concentrate (for gastrointestinal allergy)
Nedocromil sodium (Tilade)
Pulmonary aerosol: 1.75 mg/puff in 104 metered-dose container
METHYLXANTHINES: THEOPHYLLINE & DERIVATIVES
Aminophylline (theophylline ethylenediamine, 79% theophylline) (generic)
Oral: 105 mg/5 mL liquid; 100, 200 mg tablets
Rectal: 250, 500 mg suppositories
Parenteral: 250 mg/10 mL for injection
Theophylline (generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24, others)
Oral: 100, 125, 200, 250, 300 mg tablets; 100, 200 mg capsules; 26.7, 50 mg/5 mL elixirs, syrups, and solutions
Oral sustained-release, 8-12 hours: 50, 60, 75, 100, 125, 200, 250, 300 mg capsules
Oral sustained-release, 8-24 hours: 100, 200, 300, 450 mg tablets
Oral timed-release, 12 hours: 125, 130, 250, 260, 300 mg capsules
Oral timed-release, 12-24 hours: 100, 200, 300 tablets
Oral timed-release, 24 hours: 100, 200, 300 mg tablets and capsules; 400, 600 mg tablets
Parenteral: 200, 400, 800 mg/container, theophylline and 5% dextrose for injection
OTHER METHYLXANTHINES
Dyphylline (generic)
Oral: 200, 400 mg tablets; 33.3 mg/5 mL elixir
Oxtriphylline (generic, Choledyl)
Oral: equivalent to 64, 127, 254, 382 mg theophylline tablets; 32, 64 mg/5 mL syrup
Pentoxifylline (generic, Trental)
Oral: 400 mg tablets and controlled-release tablets
Note: Pentoxifylline is labeled for use in intermittent claudication only.
ANTIMUSCARINIC DRUGS USED IN ASTHMA
Ipratropium (generic, Atrovent)
Aerosol: 17 (freon-free), 18 mcg/puff in 200 metered-dose inhaler; 0.02% (500 mcg/vial) for nebulization
Nasal spray: 21, 42 mcg/spray
Tiotropium (Spiriva)
Aerosol: 18 mcg/puff in 6 packs
ANTIBODY
Omalizumab (Xolair)
Powder for SC injection, 202.5 mg
DRUGS USED IN TUBERCULOSIS
Aminosalicylate sodium (Paser)
Oral: 4 g delayed-release granules
Capreomycin (Capastat Sulfate)
Parenteral: 1 g powder to reconstitute for injection
Cycloserine (Seromycin Pulvules)
Oral: 250 mg capsules
Ethambutol (Myambutol)
Oral: 100, 400 mg tablets
Ethionamide (Trecator-SC)
Oral: 250 mg tablets
Isoniazid (generic)
Oral: 100, 300 mg tablets; syrup, 50 mg/5 mL
Parenteral: 100 mg/mL for injection
Pyrazinamide (generic)
Oral: 500 mg tablets
Rifabutin (Mycobutin)
Oral: 150 mg capsules
Rifampin (generic, Rifadin, Rimactane)
Oral: 150, 300 mg capsules
Parenteral: 600 mg powder for IV injection
Rifapentine (Priftin)
Oral: 150 mg tablets
Streptomycin (generic)
Parenteral: 1 g lyophilized for IM injection
References:
1. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication No. 07-4051. 2007.
2. National Heart, Lung, and Blood Institute. Global Strategy for Asthma Management and Prevention. NIH Publication. 2008.
3. Williams SG, Schmidt DK, Redd SC, Storms W. Key clinical activities for quality asthma care. Recommendations of the National Asthma Education and Prevention Program. MMWR Recomm Rep. Mar 28 2003;52:1-8.
4. National Heart, Lung, and Blood Institute. Education for a partnership in asthma care. Expert panel report 3: guidelines for the diagnosis and management of asthma. National Asthma Education and Prevention Program (NAEPP). Aug 2007
